1. Field of the Invention
The present invention relates to a novel series of retinobenzoic acid derivatives having retinoid-like activity. More specifically, the novel compounds of the present invention are specific agonists of RAR.gamma.. They are useful, for example, in treatment of a wide variety of dermatological conditions, e.g. acne, psoriasis, eczema and photoaging of skin, in treatment of corneopathies in opthalmology, in treatment of degenerative diseases of connective tissue, i.e. arthritis, and in the treatment of malignancies.
2. Description of the Related Art
Vitamin A is an essential nutrient for most mammalian species. It is normally supplied in the diet as retinol: ##STR2## Adequate levels of this nutrient are required for normal growth, vision and reproduction. It has been discovered that most of the effects on cellular growth and differentiation (but not the effects on vision) are mediated through the oxidized metabolite, retinoic acid: ##STR3##
Based on the structure of retinoic acid, many analogs (termed "retinoids") have been synthesized over the years as drugs for various applications. There is a vast and growing scientific literature on the chemistry, biology and clinical uses of the retinoids.
A few retinoids are already in clinical use in the treatment of dermatological diseases such as acne and psoriasis. For example, isotretinoin is used clinically for oral therapy of severe acne: ##STR4##
Retinoids have been shown to have a variety of medical uses in conditions such as acne, psoriasis, cancer, and the repair of photoaging of the skin. Despite such beneficial properties, use of the available retinoids is associated with a number of significant side effects. For example, systemic use of clinically available retinoids such as isotretinoin causes an elevation in triglyceride levels in about 1/3 of the patients treated, thus requiring periodic invasive monitoring.
The molecular basis for the activity of retinoic acid has been the subject of considerable research over the years. A major breakthrough came in recent years with the discovery of the nuclear retinoic acid receptors (RARs). These are proteins located in the cell nucleus, members of the steroid/thyroid hormone receptor superfamily. Retinoic acid binds to these proteins. Then the ligand/protein complex binds to DNA and transcription of specific genes is activated (or depressed). Genes important to cell proliferation and differentiation are among those regulated.
Three forms of the RARs have been described and termed RAR.alpha., RAR.beta. and RAR.gamma.. These receptors differ in their tissue distribution and in their times of occurrence in developing fetuses, but to date no definite difference in their functions has been observed. It has been theorized that the development of retinoids which specifically bind to and activate individual receptor subtypes would result in compounds with an improved therapeutic index compared to clinically used retinoids, which are not selective for one type over another, e.g. see WO 93/03713 and Leid, et al. in Trends in Biochemical Sciences 1992, 17, 427-433.
With regard to the retinobenzoic acid derivatives provided by the present invention, applicants are aware of the following references disclosing structurally related compounds.
U.S. Pat. No. 5,128,479 discloses retinoids of the formula ##STR5## where A may be CHOH--CH.sub.2 --X or C(.dbd.O)CH.sub.2 X, with X.dbd.N, O or S and R.sub.2 and R.sub.3 are defined to make up the fragment ##STR6## The closest of the exemplified compounds appears to be ##STR7##
In South African Patent 92/3470, there are disclosed compounds of the following generic structure: ##STR8## where R.sub.1 may be COOH, R.sub.2 is OH or O-acyl, R.sub.3 is H, OH or O-acyl, R.sub.5 and R.sub.6 may be --C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 -- and X is a variety of 3-atom fragments. The closest exemplified compound is ##STR9##
In Australian Patent No. 646314 (corresponding to WO 92/6948) are disclosed compounds of the same general structure as that of South African Patent 92/3470, but with additional exemplified compounds such as: ##STR10##
The claimed utility for retinoid compounds, including those mentioned above, is for the treatment of dermatological afflictions/disorders of keratinization, for inflammatory or allergic conditions (including the degeneration of connective tissue, i.e. arthritis), tumors, treatment of atopy (topical or systemic), psoriatic arthritis or corneopathies in opthalmology.
The compounds of the present invention may be structurally distinguished from prior art retinobenzoic acid derivatives by the mandatory inclusion of a small substituent (F, Cl, OH or CH.sub.3) at the 3-position of the terminal benzene ring (that containing the carboxyl group). Applicants have unexpectedly found that retinoid compounds which specifically activate the RAR.gamma. subtype, particularly the retinobenzoic acid derivatives provided by the present invention, have a significant advantage over non-selective retinoids in lacking the liver toxicity associated with systemic use of such retinoids.